The high level of genetic variation found in human immunodeficiency virus type 1 (HIV-1) populations is of fundamental importance to the emergence of antiretroviral drug resistance and to the challenges encountered in the development of an effective preventative or prophylactic vaccine. Both the high virus mutation rate and the high turnover rate of infected cells drive virus evolution. Recombination is also thought to play a significant role in shaping population diversity. HIV-1 replication and evolution is thought to be responsible for the gradual breakdown of the immune system and is the mechanism of disease progression to AIDS. Despite the fundamental importance of HIV-1 variation to therapy and viral pathogenesis, there are many basic concepts that remain unexplored or poorly understood. In this proposal, we seek funding to continue studies began over a decade ago. The current proposal will explore 3 lines of investigation. First, we propose to examine the interplay between the HIV-1 mutation rate and viral fitness. Although studies have been performed to analyze each, no studies have been performed to date to analyze their relationship to one another. We propose to investigate these aspects of HIV-1 replication by analysis of a small group of nucleoside and non-nucleoside reverse transcriptase inhibitor-resistant viruses that we have discovered have increased or decreased mutation rates compared to wt virus. Second, we propose to explore how adaptive mutations can alter the HIV-1 mutation rate during the selection of antiretroviral drug resistance. We will investigate whether the adaptive selection of improved viral fitness coincides with the selection for viruses that possess a wt mutation rate. Finally, we will investigate the origins of G-to-A transition mutations in HIV-1 proviruses to determine if frequent, yet sublethal cytosine deamination shapes HIV-1 variation. PUBLIC HEALTH RELEVANCE The high level variation in HIV-1 populations has led to the emergence of drug resistance and has frustrated efforts in vaccine development. A basic understanding of how HIV-1 mutates and evolves should aid in the development of new therapeutic approaches as well as improving existing ones.